HU191933B - Process for producing 8-chloro-1,5-benzothiazepine derivatives - Google Patents

Abstract

Novel 8-chloro-1,5-benzothiazepine derivatives of the formula: <IMAGE> (I) wherein R1 is hydrogen, lower alkyl or a group of the formula: R4CO-, each of R2 and R3 is lower alkyl and R4 is hydrogen or lower alkyl, and a pharmaceutically acceptable acid addition salt thereof are disclosed. Said derivative (I) and a pharmaceutically acceptable acid addition salt thereof are useful as hypotensive agents and/or coronary or cerebral vasodilators.

Description

The present invention relates to novel 8-chloro-1,5-benzothiazepine derivatives. More particularly, a process for the preparation of the compounds of formula (I) and pharmaceutically acceptable acid addition salts thereof, wherein

R ¹ is hydrogen or C 1-4 alkyl,

R ² and R ³ are both C 1 -C 4 alkyl.

U.S. Patent 3,562,257 discloses various benzothiazepine derivatives, including 7-chloro-1,5-benzothiazepine derivatives, such as 2- (4-methoxyphenyl) -3-hydroxy (or acetoxy) -5 - [2- (Dimethylamino) ethyl] -7-chloro-2,3-dihydro-1,5-benzothiazepln-4 (5H) -one. The above-mentioned patent discloses that these benzothiazepine derivatives have a sedative and / or cardiovascular dilating effect against depression.

Compounds of formula (I) and their pharmaceutically acceptable salts, according to the present invention, have been shown to have antihypertensive and / or cerebral or coronary vasodilator activity on a wide scale. In particular, the compounds of formula (I) according to the invention have a potent antihypertensive effect. For example, when spontaneously hypertensive rats (SHR) are dosed orally at 30 mg / kg with (+) - cis-2- (4-methoxyphenyl) -3-acetoxy-5- [2- (dimethylamino) ethyl] -8 -chloro-2,3-dihydro-1,5-benzothiazepin-4 (5H) -one maleate, and 1-4 hours after administration of the test compound, the SHR animals had a blood pressure reduction of 86 mmHg or 68 mmHg.

The compounds of formula (I) according to the invention also have a potent cerebral coronary vasodilator effect. For example, if (+) - cis-2- (4-methoxyphenyl) -3-acetoxy-5- [2- (dimethylamino) ethyl] -8-chloro-2,3-dihydro-1,5 Benzothiazepin-4 (5H) -one hydrochloride and (+) - cis-2- (4-methoxyphenyl) -3-propionyloxy-5- [2- (dimethylamino) ethyl] -8-chloro -2,3-dihydro-1,5-benzothiazepine-4 (5H) -one oxalate is administered intravenously to anesthetized dogs, the spinal artery blood flow is significantly increased and the compounds have a cerebral vasodilator activity about 24-25 times that of papaverine, (+) - cis-2- (4-methoxyphenyl) -3-acetoxy-5- [2- (dimethylamino) ethyl] -7-chloro-2,3-dihydro-1,5-benzothiazepine It is 5 times more potent than -4 (5H) -one hydrochloride. The coronary vasodilator effect was determined by the method of Langerdorff on isolated guinea-pig silver and tested for (+) - cis-2- (4-methoxyphenyl) -3-acetoxy-5- [2- (dimethylamino) ethyl) -8-. Chloro-2,3-dihydro-1,5-benzothiazepin-4 (5H) -one hydrochloride showed about ten times more potency than papaverine.

The compounds of formula (I) according to the invention are (+) - cis-2- (4-methoxyphenyl) -3-acetoxy-5- [2- (dimethylamino) ethyl] -7-chloro. They also have a longer-lasting therapeutic effect (i.e., a prolonged antihypertensive effect and a longer-lasting cerebral and coronary vasodilator effect) compared to -2,3-dihydro-1,5-benzothiazepin-4 (5H) -one hydrochloride.

The compounds of formula (I) produced by the process of the present invention also have potent inhibitory activity on blood vessel aggregation, show no significant side effects (e.g., on the central nervous system), and at the same time have low toxicity. For example, when administered orally to mice, (+) - cis-2- (4-methoxyphenyl) -3-acetoxy-5- [2- (dimethylamino) ethyl] -8-chloro-2,3-dihydro The acute toxicity (LD 50) value of -1,5-benzothiazepin-4 (5 H) -one hydrochloride is greater than 1000 mg / kg.

In the compounds of the present invention, R ¹ is hydrogen or lower alkyl having up to four carbon atoms, such as methyl, ethyl, propyl or butyl; and R ³ and R ³ are each independently lower alkyl having up to four carbon atoms, such as methyl, ethyl, propyl or butyl. Preferred compounds of the present invention are those wherein R ¹ is hydrogen or C 1 -C 4 alkyl, and R ² and R ³ are C 1 -C 3 alkyl. Particularly preferred compounds are those compounds of formula (I) wherein R ^{1 is} hydrogen, methyl or ethyl, R ² and R ^{3 are} methyl or ethyl, especially those wherein R ^{1 is} methyl or ethyl, R ^{2 is} methyl and R ^{3 is} methyl or ethyl, and more particularly those of formula (I) are R ¹ methyl or ethyl and R ² and R ^{3 are} methyl.

Since the compounds of formula (I) produced by the process of the invention are two stereoisomers (i.e., cis and trans isomers) and four optical isomers (i.e., (+) - cis, (-) - cis, (+) - trans and (-) - trans isomers] due to the presence of two asymmetric carbon atoms in the compound; the process of the invention also relates to all of the above isomers and mixtures thereof. However, for pharmaceutical use, the cis isomers, especially the (+) - cis isomers of the compounds of formula I are preferred.

In the process of the present invention, the compounds of formula (I) are a compound of formula (II) or a salt thereof wherein R ² and R ³ are as defined above and a compound of formula (III) or a reactive derivative thereof wherein R ¹ is by the above-described condensation reaction.

The condensation reaction of the compounds of formula (Π) or their salts with the reactive derivatives of the compounds of formula (XII) is carried out in a solvent, in the presence or absence of an acid acceptor. Suitable salts of the compounds of formula II include, for example, acid addition salts such as hydrochlorides, hydrobromides and the like. Reactive derivatives of the compounds of formula (III) include, for example, mixed acid anhydrides (such as formic acid and acetic acid), aliphatic carboxylic acid anhydrides (such as acetic anhydride, propionic anhydride) and lower aliphatic carboxylic acid (e.g. acetyl chloride, proplonyl chloride, butyryl chloride). Acid binders include pyridine, triethylamine, N-methylpiperidine, N-methylmorpholine, N-methylpyrrolidine and N-ethyl-N, N-diisopropylamine. Suitable solvents include acetic acid, chloroform, dichloromethane, dimethylformamide and tetrahydrofuran. (The reaction is preferably carried out at a temperature of -10 to 140 ° C.) If an excess of acetic anhydride is used as the reactive derivative of the compound of formula (III), a solvent is not always required because acetic anhydride also serves as a solvent. When the reactive derivative of the compound of formula (III) is a lower alkane carboxylic acid anhydride, the reaction is preferably carried out at a temperature of from 20 ° C to 140 ° C, if a mixed acid anhydride or a lower alkane carboxylic acid halide is used. At a temperature of -100 ° C.

Alternatively, when the compound of formula (III) is used in acid form in a condensation reaction with a compound of formula (II) or a salt thereof, the reaction may be carried out in a solvent in the presence of a condensing agent. The condensing agent can be dicyclohexylcarbodiimide, N, N'-carbodiimidazole, 1-methyl-2-halopyridinium iodide (e.g. 1-methyl-2-bromopyridinium iodide), methoxyacetylene and triphenylphosphine carbon tetrachloride system. Solvents used include dichloromethane, 1,2-dichloroethane, chloroform, benzene, toluene, tetrahydrofuran and dioxane. The reaction is preferably carried out at a temperature of from 0 to 50 ° C, more preferably from 0 to 25 ° C.

The starting materials of formula (II) may be present in the form of four optical isomers [(+) - cis, (-) - cis, (+) due to the presence of two asymmetric carbon atoms at the 2- and 3-positions of the benzothiazepine backbone. ) trans and (-) - trans isomer]. Since the reaction of the process of the invention described above can be carried out without the use of recrystallization, the process of the invention can readily prepare the compounds of formula I in optically active form by using the corresponding optically active compound of formula II as starting material in the process.

The starting materials of formula (II) are also novel compounds and the compound of formula (IV) and a compound of formula (V) - R ² and R ³ are as described above, can be prepared by condensation of X halogen, and the corresponding salts may also be used.

The condensation reaction of the compound (IV) or its salts with the compound (V) or their salts is carried out in a solvent. Suitable salts of the compound of formula IV include, for example, alkali metal salts such as sodium and potassium salts. When the compound of formula (IV) is used in free form, it is preferable to carry out the reaction in the presence of an alkali metal compound. A suitable alkali metal compound is, for example, an alkali metal hydroxide (such as potassium, sodium hydroxide), an alkali metal carbonate (such as potassium, sodium carbonate) or an alkali metal hydride (such as sodium hydroxide). Salts of compound (V) include, for example, acid addition salts such as hydrochloride or hydrobromide. Solvents include acetone, ethyl acetate, dimethylsulfoxide, dimethylformamide, acetonitrile, tetrahydrofuran or dioxane. The reaction is preferably carried out at a temperature of from 0 to 100 ° C, more preferably from 20 to 70 ° C.

The compounds of formula (IV) are also novel and can be prepared by Methods A, B or C.

Using process A, the compound of formula II can be prepared by reacting 2-amino-5-chlorothiophenol of formula VI with 3- (p-methoxyphenyl) glycidate of formula VII.

According to Method B, the compound of formula (IV) is reacted with (I) the 2-amino-5-chlorothiophenol of formula (VI) and a 3- (p-methoxyphenyl) glycidate of formula (VII), optionally ) by hydrolyzing the resulting propionate compound of formula VIII to the propionic acid compound of formula IX; and iiiii) by intramolecular cyclization of the compound of formula VIII or IX. According to Method C, the compound of formula IV is (i) reacted with 2-nitro-5-chlorothio-enol of formula X and a 3- (p-methoxyphenyl) glycinate of formula VII and then ii) by hydrolysis of the resulting compound of formula XI to compound of formula XII; and (iii) by reduction of compound of formula XII and (iv) by intramolecular cyclization of the compound of formula IX obtained.

In Process A, the reaction of the compound of Formula VI with the compound of Formula VII may be carried out by heating a mixture of the compound of Formula VI and the compound of Formula VII at 150-160 ° C. The reaction may be carried out in a solvent (e.g. xylene, diphenyl ether, p-cymene) or in the absence of a solvent. When the compound of formula (IV) is formed as a mixture of two stereoisomers (i.e., as a mixture of cis and trans isomers), they can be separated by their different solubilities in different solvents, such as lower alkanes (e.g. methanol), or by column chromatography.

The first step of process B, that is, the reaction of the compound of formula (VI) and the compound of formula (VII) in a solvent of a mixture of the compounds of formula (VI) and (VII) at a temperature of 40-110 ° C, particularly 60-100 ° C. heating. Suitable solvents are toluene, benzene, acetonitrile and dioxane. When the starting material is a lower alkyl trans-3- (4-methoxyphenyl) glycidate of formula (VII), the corresponding isomer of compound (VIII) is obtained.

Optional subsequent hydrolysis of the compound of formula (VIII) may be accomplished by reacting the starting material in a solvent with an alkaline reagent. Examples of alkaline reagents used are potassium hydroxide, sodium hydroxide, potassium carbonate and sodium carbonate. Suitable solvents are alkanol (e.g. methanol, ethanol) water / alkanol. The reaction is preferably carried out at a temperature of from 0 to 100 ° C, more preferably from 25 to 100 ° C.

If desired, the compound of formula (IX) thus prepared may be resolved into its optically active enantiomer by resolution using, for example, the optically active enantiomer of an optically active resolving agent, such as the (p-hydroxyphenyl) glycine ester or quinconidine. -2-hydroxy-3- (2-amino-5-chlorophenylthio) -3- (4-methoxyphenyl) propionic acid by reaction of the compound with optically active (p-hydroxyphenyl) glycine methyl ester followed by the resulting diastereomeric salts can be resolved by selective crystallization. During selective crystallization, the less soluble diastereomeric salt is recovered from the solution in crystalline form while the more soluble salt remains in solution. More specifically, in this case, for example, (+) - threo-2-hydroxy-3- (2-amino-5-chlorophenylthio) -3- (4-methoxyphenyl) propionic acid forms a less soluble diastereomeric salt of L with - (p-hydroxyphenyl) glycine methyl ester and forms (-) - threo-2-hydroxy-3- (2-amino-5-chlorophenylthio) -3- (4-methoxyphenyl) propionic acid less soluble diastereomeric salt with D- (p-hydroxyphenyl) glycine methyl ester. Selective crystallization is accomplished by recrystallization of the diastereoisomeric salts from a solvent such as a lower alkanol (e.g., methanol, ethanol). After the optical resolution, the free-form optically active compound of formula IX can be recovered from the diastereomeric salt by means of an acid (e.g. hydrochloric acid).

Intramolecular cyclization of the optically active or racemic compounds of formula (VIII) or (IX) thus obtained is accomplished by heating the compounds with or without a solvent. Suitable solvents are xylene, toluene, diphenyl ether, p-cymene and acetic acid. The reaction is preferably carried out at a temperature of 110 to 160 ° C, more preferably at reflux. Alternatively, the intramolecular cyclization of the compound of Formula VIII may be carried out at 0-50 ° C in dimethylsulfoxide in the presence of methylsulfinylcarbanion (prepared from dimethylsulfoxide and sodium hydride). Furthermore, the intramolecular cyclization of the compound of formula (IX) may also be carried out in a solvent in the presence of a condensing agent. Condensing agents include dicyclohexylcarbodiimide or 1-hydroxybenzothiazole, 4- (dimethylamino) pyridine, N-hydroxyphthalimide, N-hydroxysuccinimide, trichlorophenol, p-nitrophenol or 3-hydroxy-4 oxo-3,4-dihydro-1,2,3-benzotriazole. Carbonyldiimidazole, ethoxymethylene and 1-methyl-2-halopyridinium halide (e.g. 1-ethyl-2-chloropyridinium iodide, 1-methyl-2-bromopyridinium iodide) may also be used as condensing agents. reaction. The 1-methyl-2-halopyridinium halide condensing agent may also be used in combination with a base such as triethylamine or tributylamine.

The reaction is conveniently carried out in chloroform, dimethylformamide, carbon tetrachloride, dichloromethane, 1,2-dichloroethane, ethyl acetate, tetrahydrofuran and dioxane. The reaction is preferably carried out at a temperature of -10 to 70 ° C.

In the first step of process C, the reaction of the compounds of formula (X) and (VII) may be carried out in a solvent, in the presence or absence of a catalyst. The catalyst may be, for example, a Lewis acid such as zinc acetate, zinc iodide, zinc chloride, tin (IV) chloride, tin (IV) octylate, tin (II) chloride, tin (II) octylate, tin (II) stearate, boron trifluoride, sulfuric acid and the like. perchloric acid. Other Lewis acids described in European Patent 0 059 335 may also be used as catalysts in the reaction. Suitable solvents include toluene, benzene, xylene, dioxane, tetrahydrofuran, acetonitrile, carbon tetrachloride, chloroform and ether. The reaction is preferably carried out at a temperature of from 20 to 100 ° C, more preferably from 25 to 60 ° C. If the starting material is a lower alkyl-49 of formula VII

-trans-3- (4-methoxyphenyl) glycidate, the threoisomeric force of the compound of formula XI, is obtained.

Hydrolysis of compounds of formula (XI) may be accomplished by reaction of the compounds with alkali reagents in a solvent. Examples of alkali reagents are sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate. The solvent may be a mixture of water and a lower alkanol (e.g. methanol, ethanol, propanol), dimethylsulfoxide or dimethylformamide. The reaction is preferably carried out at a temperature of from 0 to 80 ° C, more preferably from 20 to 40 ° C.

If desired, the compound of formula (XII) thus prepared may be resolved into its optically active enanthomers by employing an optically active resolving agent (such as the optically active isomer of lysine). For example, the resolution of (±) -treo-2-hydroxy-3- (2-nitro-5-chlorophenylthio) -3- (4-methoxylphenyl) propionic acid by reacting the compound with the optically active lysine isomer and then the resulting diastereomer by selective crystallization of salts. (+) - Threo-2-hydroxy-3- (2-nitro-5-chlorophenylthio) -3- (4-methoxyphenyl) propionic acid forms with L-Ilzln and (-) - threo-2 -hydroxy-3- (2-nitro-5-chlorophenylthio) -3- (4-methoxyphenyl) propionic acid forms a less soluble diastereomeric salt with D-Ilzl. Selective crystallization is accomplished by recrystallization of diastereomeric salts from a solvent such as methyl methylformamide or a lower alcohol such as methanol. After optical resolution, the free form of the optically active compound of formula (XII) can be prepared by reaction of the resulting diastereomeric salt with an acid (e.g., hydrochloric acid, sulfuric acid, etc.).

The reduction of the racemic or optically active compound of formula (XII) thus obtained may be effected by catalytic hydrogenation of the compound or by reaction of the compound with a metal salt and an acid. The catalytic hydrogenation of the compound of formula (XII) is carried out in a solvent in the presence of a catalyst under a hydrogen atmosphere. The catalysts include, for example, palladium on activated carbon, palladium on carbon, Raney nickel and Raney cobalt catalysts. Suitable solvents include lower alkanol (e.g. methanol, ethanol, propanol), acetic acid, tetrahydrofuran, dioxane and mixtures thereof. The reaction is preferably carried out at a temperature of 20-50 ° C and a pressure of 100-2000 KPa. Alternatively, the compound of formula (XII) is reduced in a solvent with a metal or metal salt and an acid. The metal or metal salt used is, for example, tin, zinc, iron, tin (II) chloride and iron (II) sulfate. The acid used is, for example, hydrochloric acid, hydrobromic acid, acetic acid and propionic acid. Suitable solvents for the reaction are water, methanol, ethanol, acetic acid, ether, tetrahydrofuran and mixtures thereof. The reaction is preferably carried out at a temperature of from 20 to 80 ° C.

The intramolecular cyclization of the compound of formula (IX) thus prepared may be carried out according to the procedure described in Method B.

All of the reactions described above take place without racemization.

The compounds of formula (I) prepared according to the invention may be used in their free base form for pharmaceutical purposes or in the form of a pharmaceutically acceptable acid addition salt. Pharmaceutically acceptable acid addition salts of the compounds of formula I include, for example, inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, perlyloric acid, sulfuric acid or phosphoric acid, and organic acids such as oxalic acid, malonic acid, fumaric acid, many. The above salts may be prepared, for example, by acid neutralization of the compounds of formula (I). The compounds of formula (I) or their pharmaceutically acceptable acid addition salts may be administered orally or parenterally. The compounds of formula (I), or pharmaceutically acceptable acid addition salts thereof, may be used in the form of pharmaceutical compositions containing the compound, comprising pharmaceutical additives suitable for oral or parenteral administration. Suitable carriers include starch, lactose, glucose, potassium phosphate, cereal scintillator, acacia, stearic acid and other known pharmaceutical carriers. The pharmaceutical composition may be in solid form such as a tablet, pellet, capsule or suppository; or a liquid form such as a solution, suspension or emulsion. Further, for parenteral administration, the composition may be in the form of an injection.

As previously described, the compounds of formula (I) obtained by the process of the present invention have a potent antihypertensive effect, a potent coronary or coronary vasodilator effect, and a potent inhibition of platelet aggregation. Therefore, the compounds of formula (I) are useful in the treatment, amelioration or prophylaxis of hypertension, cerebrospinal disorders such as cerebral spasm or cerebral infarction and cardiac disorders such as angina pectoris, arrhythmias or coronary or heart infections, including warm-blooded animals, including man, too. Because the compounds of formula (I) produced by the process of the present invention exhibit a stronger and longer-lasting effect (antihypertensive, cerebrovascular and vascular dilator) and, at the same time, have less toxicity than that described in U.S. Patent 3,562,257. 7-chloro derivatives {e.g., (t) -511

-cis-2- (4-methoxyphenyl) -3-acetoxy-5- [2- (dimethylamino) ethyl] -7-chloro-2,3-dihydro-1,5-benzothiazepine-4 ( 5H) -one), the compounds of formula (I) obtained by the process of the present invention are much more effective antihypertensive, cerebral or coronary vasodilators than the above-mentioned 7-chloro derivative. The therapeutic dose of the compounds of formula (I) or their salts employed will depend upon the route of administration, the age, weight and condition of the patient, in particular the type of disease. However, it is generally employed at a dose of 0.05 to 10 mg / kg / day, more particularly at a dose of 0.5 to 10 mg / kg / day for oral administration and 0.05 to 2 mg / kg / day for parenteral (e.g., intravenous injection) administration. .

In the description of the process according to the invention, the term .treo is understood to mean the hydroxy and the 2-amino-5-chlorophenylthio, or the 2-ylthro-5-chlorophenylthio groups which are represented by (VIII), or The propionic acid of formula (XI) has threotype configurations at the 2- and 3-positions (i.e., in the Fischer proposal, the two groups are on the opposite side of the central bond).

First

Antihypertensive effect Time elapsed after dosing 1 hour 4 o'clock (Compounds produced by the process of the invention) (+) - cis-2- (4-methoxyphenyl) -3-acetoxy-5- [2- (dimethylamino) ethyl] -8-chloro-2,3-dihydro-1,5-benzothiazepine 4 (5H) -on maleate ++++ ++++ (±) -cis-2- (4-methoxyphenyl) -3-acetoxy- 5- [2- (dimethylamino) ethyl] -8-chloro-2,3- dihydro-l, 5-benzothiazepin-4 (5H) -one hydrochloride ++ ++++ (±) -cis-2- (4-methoxyphenyl) -3-acetoxy-5- [2- (N-methyl-N-ethylamino) ethyl] -8-chloro-2,3-dihydro- 1,5-Benzothiazepin-4 (5H) -one hydrochloride +++ +++ (Known compound) (±) -cis-2- (4-methoxyphenyl) -3-acetoxy- -5- [2- (Dimethylamino) ethyl] -7-chloro-2,3-dihydro-1,5-benzothiazepin-4 (5H) -one hydrochloride ++

Experiment 2 (Brain dilator effect)

Male dogs (10-20 kg) were anesthetized with sodium pentobarbital (30 mg / kg, intravenous injection). Spinal artery blood flow was continuously measured using an electromagnetic flowmeter,

Experiment 1 (Antihypertensive effect)

The test compound (dose: 30 mg / kg), dissolved or suspended in water, was administered orally to spontaneously hypertensive rats (SHR). These were used in groups of 3 rats and had been fasted overnight. Systolic blood pressure was measured in rats using a technique for monitoring blood congestion (Journal of Laboratory and Clinical Medicine 78: 957 (1971)). The antihypertensive effect of the test compound was evaluated one to four hours after dosing. This if the decrease in blood pressure below 10 mm Hg. + 'Rated, if the decrease is 10 mmHg greater than ²⁰ but less than 20 mm Hg. ++' rated when the vérnyomsácsökkenés greater than 20 mm Hg, but less than 40 mmHg, rated at +++ 'if the blood pressure is greater than 40 mmHg, but less than ²⁵ 63 mmHg, and. ++++' if the blood pressure is greater than 60 mmHg.

The results of the experiment are summarized in Table 1.

Table while breathing was artificially maintained. The test compound was dissolved in 5% aqueous glucose solution and injected into the spinal artery. The cerebrovascular effect of the compound was estimated in relation to the effect of papaverine, calculated from the dose-response curve of the compound and papaverine.

The results of this experiment are shown in Table 2 65.

-613

Table 2

Test compound Mouse expanding effect (effect ratio) (Compounds of the Invention) (+) - cis-2- (4-methoxyphenyl) -3-acetoxy-5- - [2- (dimethylamino) ethyl] -8-chloro-2,3- dihydro-l, 5-benzothiazepin-4 (5H) -one hydrochloride 25 (+) - cis-2- (4-methoxyphenyl) -3-propionyloxy-5- - [2-dimethylamino) ethyl] -8-chloro-2,3-dihydro- -1,5-benzothiazepine-4 (5H) -one oxalate 23.7 (Known compound) (±) -cis-2- (4-methoxyphenyl) -3-acetoxy-5- [2- (dimethylamino) ethyl] -8-chloro-2,3-dihydro-1,5-benzothiazepine -4 (5H) -one hydrochloride 5 (Positive control) papaverine 1

Experiment 3

Male dogs of 20-24 kg (2 animals per group) were anesthetized (35 mg / kg, intravenous injection) with sodium pentabarbital. Spinal artery blood flow was continuously measured using an electromagnetic flowmeter while breathing was maintained artificially. Substance to be tested {e.g. (+) - cis-2- (4-methoxyphenyl) -3-acetoxy-5- [2- (dimethylamino) ethyl] -8-chloro-2,3-dihydro-1 , 5-benzothiazepin-4 (5H) -one hydrochloride] in physiological saline at a dose of 200 micrograms / kg was injected into the femur. The cerebral vasodilator activity was expressed as the increase in spinal artery blood flow (δ ml / min) obtained by subtracting the blood flow measured immediately before the administration of the test compound from the blood flow measured at the time after administration.

The results are summarized in Table 3.

Table 3

Time (minutes) after administration of test compound Increase in spinal artery blood flow (δ ml / min) 1 58 3 53 5 52 10 38 20 21 30 14

Experiment 4 (coronary vasodilator effect)

The effect on the coronary blood flow of isolated guinea-pig heart (about 280 g) was investigated for the compounds of the invention according to the Langendorff method. The isolated pig was injected with a Locke-Ringer solution containing 2% fib35 rabbit free rabbit (perfused) and saturated with a gas mixture containing 95% oxygen and 5% carbon dioxide at 30 ° C. The perfusion pressure was maintained at 40 of my water. A solution of the test compound in 5% aqueous glucose solution was injected into the perfusion solution at a volume of 0.1 ml / heart volume. The amount of perfusion outlet solution was then measured using a drop counter.

Coronary vasodilator effect of test compound ± if coronary artery blood flow increase is less than 0.5 ml / min at 100 microgram / ml dose; + ', If the coronary blood flow increase is not less than 0.5 ml / min at 100 micrograms / heart dose; . ++ 'if coronary blood flow increase is not less than 0.5 ml / min at a dose of 30 micrograms / heart and +++' if coronary blood flow increase is not less than 0.5 ml / min at a dose of 10 micrograms / heart.

The results are summarized in Table 4 below.

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Table 4

Test compound

Coronary heart disease (Compounds of the invention) (+) - cis-2- (4-methoxyphenyl) -3-acetoxy-5- [2- (dimethylamino) ethyl] -8-chloro 2,3-dihydro-

l, 5-benzothiazepin-4 (5H) -one hydrochloride +++ (±) -cis-2- (4-methoxyphenyl) -3-acetoxy-5- [2- (dimethyl-amino) ethyl] -8-chloro-2,3-dihydro-1,5-benzothiazepine 4 (5H) -on-hi d hydrochloride +++ (±) -cis-2- (4-methoxyphenyl) -3-acetoxy-5- [2- (N-methyl-N-propylamino) ethyl] -8-chloro-2,3-dihydro- 1,5-Benzothiazepine-4 (5H) -one oxalate +++ (Positive control) papaverine +

Experiment 5 (Platelet aggregation inhibitory effect)

Male Sprague-Dawley blood was drawn from the abdominal aorta of rats anesthetized with ether. Ninety volumes of rat blood were mixed with one volume of aqueous trisodium citrate solution and centrifuged to give platelet rich plasma (.PRP) as the supernatant of the solution. The lower layer was further centrifuged to give a platelet-poor plasma (.PPP) as a supernatant. Plasma concentration of PRP plasma was adjusted to 0.8 x 10 ⁶ / mm ³ using PPP plasma. A mixture of 200 microliters of diluted PRP and 25 microliters of test compound to a final concentration of 100 micrograms / ml was then stirred for 2 minutes at 37 ° C, followed by 25 microliters of collagen solution [Biochim. Biophys. Acta 186, 254 (1969)]. Platelet aggregation was determined by the method of Born (Natura, 194, 927 (1962)) and the percentage inhibition of platelet aggregation was calculated. The inhibitory effect of the test compound on platelet aggregation when the compound exhibits less than 10% inhibition of platelet aggregation, + 'if the test compound exhibits at least 10% inhibitory activity on platelet aggregation but less than the effect of acetylsalicylic acid (100 micrograms / ml); or. ++, if the inhibitory effect of the test compound on platelet aggregation is at least as strong as that of acetylsalicylea (100 micrograms / ml).

The results of the experiment are summarized in Table 5.

Table 5

Test compound Platelet aggregation inhibitory effect (Compounds of the Invention) (±) -Cis-2- (4-methoxyphenyl) -3-acetoxy-5- [2-dimethylamino) ethyl] -8-chloro-2,3-dihydro-1,5-benzothiazepine -4 (5H) -one hydrochloride ++ (±) -cis-2- (4-methoxyphenyl) -3-acetoxy-5- [2- (N-methyl-N-propylamino) ethyl] -8-chloro-2,3-dihydro -1,5-benzothiazepine-4 (5H) -one oxalate ++ (+) - Cis-2- (4-methoxyphenyl) -3-acetoxy-5- [2- (diethylamino) ethyl] -8-chloro-2,3-dihydro-1,5-benzothiazepine -4 (5H) -one oxalate ++ (+) - cis-2- (4-methoxyphenyl) -3-propionyloxy-5- [2- (dimethylamino) ethyl] -8-chloro-2,3-dihydro-1,5- benzothiazepine-4 (5H) -one oxalate ++

-817

Example 1 (1) 6.8 g of (+) - cis-2- (4-methoxyphenyl) -3-hydroxy-8-chloro-2,3-dihydrobenzothiazepin-4 (5H) -one, A mixture of 02 g of 2- (dimethylamino) ethyl chloride hydrochloride, 6.1 g of potassium carbonate and 150 ml of acetone is refluxed for 20 hours. After the reaction was complete, the insoluble material was filtered off and washed with ethanol. The washings were combined with the filtrate and the combined solution concentrated in vacuo. The residue was dissolved in ethyl acetate and the solution was washed with water, dried and evaporated. The residue was recrystallized from ethyl acetate-hexane. 7.13 g of (+) - cis -2- (4-methoxyphenyl) -3-hydroxy-5- [2- (dimethylamino) ethyl] -8-chloro-2,3-dihydro-1, 5-Benzothiazepin-4 (5H) -one is obtained as a needle crystalline material.

Mp 122-124 ° C (dec.).

[α] D ²⁰ + 144.6 ° (C = 0.85, methanol)

oxalate:

M.p. 201-203 ° C (dec.), (Recrystallized from chloroform, ethanol, ether mixture).

[α] D ²⁰ + 78.4 ° (C = 0.74, dimethylformamide).

(2) 6.4 g of (+) - cis -2- (4-methoxyphenyl) -3-hydroxy-5- [2- (dimethylaminyl) ethyl] -8-chloro-2,3-dihydro A mixture of -1,5-benzothiazepin-4 (5H) -one, 65 ml of acetic anhydride and 0.7 ml of pyridine was evaporated for 3 hours at 110 ° C. The residue was converted to the hydrochloric acid salt and recrystallized from a mixture of acetone and ethanol. 4.7 g of (+) - cis-2- (4-methoxyphenyl) -3-acetoxy-5- [2- (dimethylamino) ethyl] -8-chloro-2,3-dihydro-1, 5-Benzothiazepin-4 (5H) -one hydrochloride is obtained.

127-131 ° C (decomposition) (α) d ²⁰ + 92.2 ° (C = 0.796, ethanol)

Elemental analysis for C22H25O4SCI.HCI.I / 2H2O:

Calculated: C, 53.44; H, 5.50; N, 5.67. Cl, 14.34; Found: C, 53.11; H, 5.38; N, 5.60; Cl, 13.98.

maleate:

Needle, crystalline material (recrystallized from ethanol).

Mp: 158-160 ° C, (α) d ²⁰ + 75.4 ° (C = 1.0, methanol)

fumarate

Needle, crystalline material (recrystallized from a mixture of ethanol and ether).

M.p .: 199-201 ° C (dec.).

methane sulfonate:

Prismatic crystalline material (recrystallized from a mixture of ethanol and ether).

Mp 147-149 ° C

Elemental analysis for C23H29O7N2S2Cl.H2O:

Calculated: C, 49.05; H, 5.55; N, 4.62; S, 11.38;

Cl, 6.29;

Found: C, 48.88; H, 5.42; N, 5.03; S, 11.38;

Cl, 6.38.

Example 2 (1) 6.4 g of (-) - cis-2- (4-methoxyphenyl) -310

-hydroxy-8-chloro-2,3-dihydro-1,5-benzothiazepin-4 (5H) -one, 3.0 g of 2- (dimethylamino) ethyl chloride hydrochloride, 5.8 g of potassium carbonate and 150 ml the acetone mixture is reacted according to the procedure of Examples 1- (1). The crude product was recrystallized from ethyl acetate-hexane and 6.93 g of (-) - cis-2- (4-methoxyphenyl) -3-hydroxy-5- [2- (dimethylamino) ethyl] - 8-Chloro-2,3-dihydro-1,5-benzothiazepin-4 (5H) -one is obtained as a colorless, needle-like crystalline solid.

Mp 121-123 ° C (dec.).

[α] D ²⁰ : -142.7 ° (C = 1.04, methanol).

oxalate:

M.p. 202-204 ° C (dec.), (Recrystallized from a mixture of chloroform-ethanol-ether).

[α] D ²⁰ : -78.4 ° (C = 0.88, dimethylformamide).

(2) 6.35 g of (-) - cis-2- (4-methoxyphenyl) -3-hydroxy-5- [2- (dimethylamino) ethyl] -8-chloro-2,3-dihydro A mixture of -1,5-benzothiazepin-4 (5H) -one, 65 ml of acetic anhydride and 0.7 ml of pyridine was reacted according to the procedure of Examples 1- (2), and the product was converted to the hydrochloric acid salt and recrystallized from acetone. (-) - cis-2- (4-methoxyphenyl) -3-acetoxy-5- [2- (dimethylamino) ethyl] -8-chloro-2,3-dihydro-4.28 g, 5-Benzothiazepin-4 (5H) -one hydrochloride is obtained.

Mp 128-132 ° C (dec.).

(oc) d ^z °: -93.3 ° (C = 0.872, ethanol).

Elemental analysis for C22H25O4N2SCI. According to the formula I / 2H2O:

Calculated: C, 53.44; H, 5.50; N, 5.67. Cl, 14.34; Found: C, 53.17; H, 5.45; N, 5.59; Cl, 14.28.

Example 3 (1) 6.72 g of (±) -cis (4-methoxyphenyl) -3-hydroxy-8-chloro-2,3-dihydro-1,5-benzothiazepin-4 (5H) -one A mixture of potassium hydroxide (2.58 g) and dimethyl sulfoxide (90 ml) was stirred at room temperature for 1 hour. 2.16 g of 2- (dimethylamino) ethyl chloride hydrochloride are then added and the mixture is stirred at room temperature for 16 hours. The mixture was then poured into ice water and the precipitated crystalline material was filtered off, washed with water and then dissolved in concentrated hydrochloric acid. The solution was washed with ethyl acetate and basified with potassium carbonate. The solution was then extracted with chloroform. The extract was washed with water, filtered and evaporated. The residue was converted to the hydrochloric acid salt and recrystallized from ethanol. 6.65 g of (±) -cis-2- (4-methoxy-phenyl) -3-hydroxy-5-1,2-dimethylamino-ethyl] -8-chloro-2,3-dihydro-1 5-Benzothiazepin-4 (5H) -one hydrochloride is obtained. The product was recrystallized from a mixture of chloroform-ethanol-ether to give a prismatic crystalline solid, m.p. 136-139 ° C.

Elemental analysis for C20H23O3N2SCIHCl.I / 2H2O:

Calculated: C, 53.96; H, 5.82; N, 5.99; Cl, 15.17;

-919 found: C, 53.61; H, 5.94; N, 6.00; Cl, 15.31.

(2) 1 g of (±) -cis-2- (4-methoxyphenyl) -3-hydroxy-5- [2- (diraethylamino) ethyl] -8-chloro-2,3-dihydro-1 A mixture of 5-benzothiazepin-4 (5H) -one hydrochloride, 2 ml acetic anhydride and 2 ml acetic acid was stirred at 110 ° C for 4 hours and then concentrated in vacuo. Ether was added to the residue and the crystalline material was filtered off. 1.08 g of (±) -cis-2- (4-methoxyphenyl) -3-acetoxy-5- [2- (dimethylamino) ethyl] -8-chloro-2,3-dihydro -1,5-benzothiazepin-4 (5H) -one hydrochloride is obtained. The material was recrystallized from chloroform-ethanol-ether to give a needle-crystalline product; mp: 159-15-1161 ° C.

Elemental analysis for C22H25N2O4SCl.HCIC2H5OH:

calcd: C, 54.23; H, 5.88; N, 5.27; Cl, 13.34;

Found: C, 53.99; H, 5.70; N, 5.47; Cl, 13.45. 20

Example 4 With another method of Example 3- (1), the product was converted to the hydrobromide and recrystallized from a mixture of ethanol and ether.

2.1 g of colorless prismatic crystalline (±) -cis-2- (4-methoxyphenyl) -3-hydroxy-5- [2-N-methyl-N-propylamino) ethyl] -8- Chloro-2,3-dihydro-1,5-one is obtained with n-thiazepin-4 (5H) -one hydrobromide.

M.p. 82-83 ° C (dec.).

(2) 0.82 g of (±) -cis-2- (4-methoxyphenyl) -3-hydroxy-5- [2- (N-methyl-N-propylamino) ethyl] -8-chloro A mixture of -2,3-dihydro-1,5-benzothiazepin-4 (5H) -one, 10 ml of acetic anhydride and 1 ml of pyridine was stirred for 3 hours at 100 ° C and the solvent was distilled off. The residue is converted to the oxalate and recrystallized from chloroform-ethanol. 0.75 g of needle colorless crystals of (±) -cis-2- (4-methoxyphenyl) -3-acetoxy-5- [2- (N-methyl-N-propylamino) ethyl] -8 Chloro-2,3-dihydro-1,5-benzothiazepin-4 (5H) -one oxalate is obtained.

M.p .: 197-198 ° C (dec.).

(1) 3 g of (±) -cis-2- (4-methoxyphenyl) -3-hydroxy-8-chloro-2,3-dihydro-1,5-benzothiazepin-4 (5H) -one and 7 g of 2- (N-methyl-N-ethylamino) ethyl chloride hydrochloride was reacted according to the procedure of Example 5. The product is converted to the hydrochloride and recrystallized from a mixture of ethanol and ether. 3.1 g of (±) -cis-2- (4-methoxyphenyl) -3-hydroxy-5- [2- (N-methyl-N-ethylamino) ethyl] -8-chloro-2, 3-Dihydro-1,5-benzothiazepin-4 (5H) -one hydrochloride was obtained as a colorless, needle-like crystal.

Mp 132-135 ° C (dec.).

Elemental analysis for C21H25O3N2SCl.HCl1 / 2H2O:

calcd: C, 54.07; H, 5.84; N, 6.01; Cl, 15.20; Found: C, 54.32; H, 5.88; N, 5.76. Cl, 15.31.

(2) 0.9 g of (±) -cis-2- (4-methoxyphenyl) -3-hydroxy-5- [2- (N-methyl-N-ethylamino) ethyl] -8-chloro -2,3-Dihydro-1,5-benzothiazepin-4 (5H) -one hydrochloride, 5 ml acetic anhydride and 5 ml acetic acid were reacted according to the procedure of Example 3- (2) and the crude product was mixed with chloroform-ethanol-ether solvent mixture. átkristólyositjuk. 0.9 g of tus, crystalline (±) -cis-2- (4-methoxyphenyl) -3-acetoxy-5- [2- (N-methyl-N-ethylamino) ethyl] -8-chloro -2,3-dihydro-1,5-benzothiazepin-4 (5H) -one hydrochloride is obtained.

Mp 229-232 ° C (dec.).

Elemental analysis for C23H27N2O4SCl.HCl I / 2H2O:

calcd: C, 54.22; H, 5.75; N, 5.51; Cl, 13.95; Found: C, 53.97; H, 5.82; N, 5.87. Cl, 13.73.

Example 5 (1) 2 g of (±) -cis-2- (4-methoxyphenyl) -3-hydroxy-8-chloro-2,3-dihydro-1,5-benzothiazepin-4 (5H) -one and 1.13 g of 2- (N-methyl-N-propylamino) ethyl chloride hydrochloride are reacted with

Example 6 (1) 2.5 g of (+) - cis-2- (4-methoxyphenyl) -3-hydroxy-8-chloro-2,3-dihydro-1,5-benzothiazepine-4 (5H) a mixture of 1.3 g of 2- (N-methyl-N-ethylamino) ethyl chloride hydrochloride, 3.01 g of potassium carbonate and 35 ml of acetone is refluxed for 21 hours. The insoluble material was filtered off and the filtrate was concentrated in vacuo. The residue is converted to the perchlorate and recrystallized from ethanol. 3.24 g of (+) - cis-2- (4-methoxyphenyl) -3-hydroxy-5- [2- (N-methyl-N-ethylamino) ethyl] -8-chloro-2, 3-Dihydro-1,5-benzothiazepin-4 (5H) -one perchlorate is obtained.

⁴⁰ ° C: 197-201 ° C (α) d ²⁰ : + 80.6 ° (C = 0.5, methanol).

(2) 2.74 g of (+) - cis -2- (4-methoxyphenyl) -3-hydroxy-5- [2- (N-methyl-N-ethylamino) ethyl] -8- ⁴⁵ A mixture of chloro-2,3-dihydro-1,5-benzothiazepin-4 (5H) -one, ml of acetic anhydride and 12 drops of pyridine was heated at 100 ° C for 3 hours and then concentrated in vacuo. The residue was dissolved in ether and the solution was extracted with dilute hydrochloric acid. The extract was washed with ether, basified with 10% sodium hydroxide solution and extracted with chloroform. The chloroform solution was washed with water, dried and then concentrated in hot heat. The residue was converted into L-tartrate and recrystallized from ethanol.

3.28 g of (+) - cis-2- (4-methoxyphenyl) -3-acetoxyl-5- [2- (N-methyl-N-ethylamino) ethyl] -8-chloro-2, 3-Dihydro-1,5-benzothiazepin-4 (5H) -one-L-tartrate is obtained.

Mp 128-133 ° C (dec.).

[α] D ²⁰ : + 84.0 ° (C = 1.0, methanol).

Example 7 (1) 1.01 g of (+) - Nis-2- (4-methoxyphenyl) -311

-1 021

-hydroxy-8-chloro-2,3-dihydro-1,5-benzothiazepin-4 (5H) -one, 0.57 g of 2- (diethylamino) ethyl chloride hydrochloride, 1.24 g of potassium carbonate and 30 ml of acetone were reacted according to the procedure of Example 6- (1). The product is converted to fumarate and recrystallized from ethanol (1.22 g) (+) - cis-2- (4-methoxyphenyl) -3-hydroxy-5- [2- (diethylamino) ethyl] -8-chloro 2,3-dihydro-1,5-benzothiazepin-4 (5H) -one fumarate is obtained.

Mp 146-147.5 ° C.

(dc) d ²⁰ : +91.0 (C = 1.0, methanol).

(2) 0.67 g of (+) - cis-2- (4-methoxyphenyl) -3-hydroxy-5- [2- (diethylamino) ethyl] -8-chloro-2,3-dihydro -1,5-Benzothiazepin-4 (5H) -one, 7 ml acetic anhydride and 2 drops of pyridine were reacted according to the procedure of Example 6- (2). The product is converted to the oxalate and recrystallized from ethanol to give 0.634 g of (+) - cis-2- (4-methoxyphenyl) -3-acetoxy-5- [2- (diethylamino) ethyl] -8-chloro-2,3 -dihydro-1,5-benzothiazepine-4 (5H) -one oxalate is obtained.

M.p .: 183-184.5 ° C (dec.).

[α] D ²⁰ : + 86.6 ° (C = 1.0, methanol).

Example 8.

0.8 g of (+) - cis -2- (4-methoxyphenyl) -3-hydroxy-5- [2- (dimethylamino) ethyl] -8-chloro-2,3-dihydro-1, A mixture of 5-benzothiazepin-4 (5H) -one, 9 ml of formic acid, 3 ml of acetic anhydride and 1 ml of pyridine was stirred at room temperature for 3 days. The reaction mixture is then concentrated in vacuo, the residue is converted to the oxalate and recrystallized from ethanol / ether. 0.725 g of (+) - cis-2- (4-methoxyphenyl) -3-formyloxy-5- [2- (dimethylamino) ethyl] -8-chloro-2,3-dihydro-1,5 benzothiazepine-4 (5H) -one oxalate is obtained.

Mp 180-183 ° C (dec.).

[α] D ²⁰ : + 117.8 ° (C = 1.0, dimethylformamide).

Example 9 g (+) - cis-2- (4-methoxyphenyl) -3-hydroxy-5- [2- (dimethylamino) ethyl-8-chloro-2,3-dihydro-1,5 A mixture of benzothiazepin-4 (5H) -one, 0.47 g propionyl chloride and 20 ml pyridine was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo, the residue converted to oxalate and recrystallized from acetone. 0.947 g of (+) - cis-2- (4-methoxyphenyl) -3-propionyloxy-5- [2- (dimethylamino) ethyl] -8-chloro-2,3-dihydro-1,5 benzothiazepine-4 (5H) -one oxalate is obtained.

M.p .: 130 ° C (dec.).

[α] D ²⁰ : +85.82 ° (C = 1, dimethylformamide).

Example 10

900 mg of (+) - cis-2- (4-methoxyphenyl) -3-hydroxy-5-2- (dimethylamino) ethyl] -8-chloro-2,3- ¹²

A mixture of -dihydro-1,5-benzothiazepin-4 (5H) -one, 300 mg of butyryl chloride and 1 ml of pyridine was reacted according to the procedure of Example 9. The product is converted to the oxalate and recrystallized from ethanol. 1.216 g of (+) - cis-2- (4-methoxyphenyl) -3-butyryloxy-5- [2- (dimethylamino) ethyl] -8-chloro-2,3-dihydro-1,5 benzothiazepine-4 (5H) -one oxalate is obtained.

Mp: 140-142 ° C.

(α) d ²⁰ : + 61.28 ° (C = 0.320, methanol).

Example 11

900 mg of (+) - cis-2- (4-methoxyphenyl) -3-hydroxy-5- [2- (dimethylamino) ethyl] -8-chloro-2,3-dihydro-1,5 Benzothiazepin-4 (5H) -one, 300 mg of valeryl chloride and 1 ml of pyridine were reacted according to the procedure of Example 9 and the crude product was converted to the oxalate and then recrystallized from ethanol. 1.218 g of (+) - cis-2- (4-methoxyphenyl) -3-valeryloxy-5- (2- (dimethylamino) ethyl-8-chloro-2,3-dihydro-1,5-benzothiazepine -4 (5H) -one oxalate is obtained.

Mp: 167-169 ° C.

(tt) D ²⁰ + 56.4 ° (C = 0.328, methanol).

Preparation of starting materials

1. Production

A mixture of 20.3 g of 2-amino-5-chlorothiophenol and 26.4 g of methyl (±) -3- (4-methoxyphenyl) glycidate was stirred at 160 ° C for 16 hours under argon. . The reaction mixture was cooled and ethanol was added. The precipitated crystalline material is filtered off and washed with ethanol. 11.3 g of (±) -cis-2- (4-methoxyphenyl) -3-hydroxy-8-chloro-2,3-dihydro-1,5-benzothiazepin-4 (5H) -one are obtained.

Mp 230-232 ° C.

The product is recrystallized from dimethylformamide to give a needle crystalline solid; mp 230-232 ° C.

The mother liquor of the ethanol solution was evaporated to dryness in vacuo and the residue was dissolved in ethyl acetate. The solution was washed with 10% hydrochloric acid, water, saturated aqueous sodium bicarbonate solution, and then again with water. The reaction mixture was concentrated and the residue was purified by chromatography on silica gel (eluent: chloroform). 0.8 g of (±) -cis-2- (4-methoxyphenyl) -3-hydroxy-8-chloro-2,3-dihydro-1,5-benzotaphazepin-4 (5H) -one (cis isomer) 1.5 g of (±) -trans-2- (4-methoxyphenyl) -3-hydroxy-8-chloro-2,3-dihydro-1,5-benzothiazepin-4 (5H) -one (trans- isomer).

Cis isomer:

Mp 230-232 ° C.

Trans isomer:

Needle, crystalline material, recrystallized from ethyl acetate-hexane solvent mixture.

M.p .: 183-185 ° C.

-1 123

Preparation 2 (1) 63.1 g of 2-amino-5-chlorothiophenol,

A mixture of 90.4 g of methyl (±) -trans-3- (4-methoxyphenyl) glycidate and 600 ml of toluene was stirred at 65-70 ° C for 40 hours and then cooled. The precipitated crystalline material is filtered off. 71.7 g of methyl (±) -threo-2-hydroxy-3- (2-amino-5-chlorophenylthio) -3- (4-methoxyphenyl) propinate are obtained.

Mp: 131-132 ° C.

The product was recrystallized from ethyl acetate-hexane to give a needle crystalline solid; mp 131-132 ° C.

(2) 23.5 g of methyl (±) -threo-2-hydroxy-3- (2-amino-5-chlorophenylthio) -3- (4-methoxyphenyl) propionate, 150 ml of 5% NaOH (150 mL) and methanol (150 mL) were stirred for 2 hours at room temperature. The reaction mixture was then adjusted to pH 4 with dilute hydrochloric acid and the precipitate was filtered off. The crystalline material was washed with water and recrystallized from a mixture of ethanol-dimethylformamide solvent,

17.5 g of (±) -treo-2-hydroxy-3- (2-amino-5-chlorophenylthio) -3- (4-methoxyphenyl) propionic acid are obtained. Ink, crystalline material: op. 189-191 ° C (dec.).

(3) A mixture of (±) -treo-2-hydroxy-3- (2-amino-5-chlorophenylthio) -3- (4-methoxyphenyl) propionic acid (2 g) in xylene (150 ml) was refluxed for 25 hours. while boiling, remove the resulting water with a water separating cap. The reaction mixture is then cooled and the precipitated crystalline material is filtered off. The product was recrystallized from dimethylformamide to give 1.6 g of (±) -cis-2- (4-methoxyphenyl) -3-hydroxy-8-chloro-2,3-dihydro-1,5-benzothiazepine-4 (5H) -. ont kapunk.

Mp 230-232 ° C.

3. Production

Dissolve 450 g of methyl (±) -threo-2-hydroxy-3- (2-amino-5-chlorophenylthio) -3- (4-methoxyphenyl) propionate in 1.5 ml of dimethyl sulfoxide and At a temperature below 15 ° C, it was added to a solution of methylsulfinylcarbanion (3ml) in dimethylsulfoxide (103mg) and sodium hydride (60mg, 60% in oil). The reaction mixture was stirred at room temperature for 40 minutes and then poured into 190 mg of acetic acid in ice.

The precipitated crystalline material is filtered off, washed with water, dried and recrystallized from dimethylformamide. 300 mg of (±) -cis-2- (4-methoxyphenyl) -3-hydroxy-8-chloro-2,3-dihydro-1,5-benzothiazepin-4 (5H) -one are obtained.

The product has the same physico-chemical characteristics as the material obtained in Preparation 2 - (3).

Preparation 4 (1) 30.5 g of L- (p-hydroxyphenyl) glycine methyl ester hydrochloride are dissolved in 600 ml of methanol and a solution of 7.85 g of potassium hydroxide in 150 ml of methanol is added. The insoluble precipitate was filtered off. To the filtrate was added a solution of (±) -treo-2-hydroxy-3- (2-amino-5-chlorophenylthio) -3- (4-methoxyphenyl) propionic acid (24.7 g) in ethanol (900 mL) and the mixture was evaporated at a temperature below 60 ° C. The residue was dissolved in ethanol (500 mL) and the insoluble precipitate was filtered off. The filtrate was allowed to stand overnight at room temperature, concentrated in vacuo and the residue recrystallized from ethanol (the mother liquor hereinafter referred to as .1 mother liquor). The crystalline material thus obtained is recrystallized from ethanol. 14.3 g of (+) - t: -eo-2-hydroxy-3- (2-amino-5-chlorophenylthio) -3- (1-methoxyphenyl) propionic acid L- (p-hydroxy) phenr) glycine methyl ester salt is obtained.

Mp 169-172 ° C (dec.).

[α] D ²⁰ : + 316.7 ° (C = 1.14, dimethylformamide).

The product thus obtained (14.3 g) was acidified by adding 10% hydrochloric acid and the aqueous mixture was concentrated in vacuo. Water was added to the residue and the precipitated crystalline material was filtered off, washed with water and dried. 7.8 g of (+) - threo-2-hydroxy-3- (2-amino-5-chlorophenylthio) -3- (4-methoxyphenyl) propionic acid are obtained.

Mp 173-175 ° C (dec.).

(α) D ²⁰ : + 325.0 ° (C = 0.73, nNaOH).

The resulting mother liquor I was concentrated in vacuo and the residue acidified with 10% hydrochloric acid. The precipitate was filtered off. The resulting crystalline material (15.5 g), 4.92 g of potassium hydroxide and 19.1 g of D- (p-hydroxyphenyl) glycine methyl ester hydrochloride are reacted as described above. 13.9 g of (-) - threo-2-hydroxy-3- (2-amino-5-chlorophenylthio) -3- (4-methoxyphenyl) propionic acid E- (p-hydroxyphenyl) - glycine methyl ester salt.

Mp 168-171 ° C (dec.).

(a) D ²⁰ : -316.5 ° (C = 1.342, dimethylformamide).

The product (13.9 g) was converted to the free acid form by the above method with 10% hydrochloric acid. 7.3 g of (-) - threo-2-hydroxy-3- (2-amino-5-chlorophenylthio) -3- (4-methoxyphenyl) propionic acid are obtained.

Mp 172-174 ° C (dec.).

(α) D ²⁰ : -323.4 ° (C = 0.93, nNaOH).

(2-a) A mixture of 10 g of (+) - threo-2-hydroxy-3- (2-amine-5-chlorophenylthio) -3- (4-methoxyphenyl) propionic acid in 600 ml of xylene over reflux. It is then cooled and the precipitated crystalline material is filtered off.

-1 225

6) 9 g of (+) - cis -2- (4-methoxyphenyl) -3-hydroxy-8-chloro-2,3-dihydro-1,5-benzothiazepin-4 (5H) -one are obtained.

Mp 236-239 ° C (dec.).

[α] D ²⁰ : + 92.1 ° (C = 1.02, dimethylformamide).

(2-b) A mixture of 9 g of (-) - threo-2-hydroxy- (2-amino-5-chlorophenylthio) -3- (4-methoxyphenyl) propionic acid in 500 ml of xylene ) and 6.5 g of (-) - cis-2- (4-methoxyphenyl) -3-hydroxy-8-chloro-2,3-dihydro-1,5-benzothiazepine-4 (5H). -on.

Mp 235-237 ° C (dec.).

[α] D ²⁰ : -92.0 ° (C = 1.06, dimethylformamide).

5. Preparation (1-a) 19.75 g of 2-nitro-5-chlorothiophenol and

27.6 g of methyl (±) - trans-3- (4-methoxyphenyl) glycidate are suspended in 200 ml of toluene and 500 mg of zinc acetate dihydrate are added. The reaction mixture was stirred at room temperature for 3 hours and then concentrated in vacuo. To the residue is added isopropyl ether and the solid is filtered off. The crystalline material is washed with water and then with isopropyl ether and then recrystallized from a mixture of benzene-isopropyl ether solvent.

27.66 g of needle crystalline methyl (±) -threo-2-hydroxy-3- (2-nitro-5-chlorophenylthio) -3- (4-methoxyphenyl) propinate are obtained.

Mp: 141-143 ° C.

(1- b) 1.7 g of 2-nitro-5-chlorothiophenol,

A mixture of 2.38 g of methyl (±) -trans-3- (4-methoxyphenyl) glycidate, 17 ml of toluene and 0.05 ml of tin (II) chloride is reacted according to the procedure described in (1-a). 2.21 g of methyl (±) -threo-2-hydroxy-3- (2-nitro-5-chlorophenylthio) -3- (4-methoxyphenyl) propionate are obtained.

Mp: 141-143 ° C.

(1-c) 1.7 g of 2-nitro-5-chlorothiophenol,

Methyl (±) -trans-3- (4-methoxyphenyl) glycidate (2.38 g), toluene (17 ml) and tin (II) chloride (30 mg) were reacted according to the procedure described in (1-a) and 1.933 g. methyl (±) -threo-2-hydroxy-3- (2-nitro-5-chlorophenylthio) -3- (4-methoxyphenyl) propionate is obtained.

Mp: 141-143 ° C.

(1-d) 1.7 g of 2-nitro-5-chlorothiophenol,

A mixture of 2.38 g of methyl (±) -trans-3- (4-methoxyphenyl) glycidate, 20 ml of toluene and 0.05 ml of tin (II) octylate is reacted according to the procedure of (1-a). 14 g of methyl (±) -treo-2-hydroxy-3- (2-nitro-5-chlorophenylthio) -3- (4-methoxyphenyl) propionate are obtained.

Mp: 141-143 ° C.

(2) 22.0 g of methyl (±) -threo-2-hydroxy-3- (2-nitro-5-chlorophenylthio) -3- (4-ethoxyphenyl) propionate, 120 ml of 10% sodium hydroxide and 400 ml of methanol were stirred at room temperature for 5 hours. The reaction mixture is then acidified with concentrated hydrochloric acid and the precipitated crystalline material is filtered off. The crystalline material was washed with water, dried and recrystallized from ethanol. 17.49 g of (+) - threo-2-hydroxy-3- (2-nitro-5-chlorophenylthio) -3- (4-methoxyphenyl) propionic acid are obtained in the form of a plate crystalline material.

Mp: 179-182 ° C.

(3) 350 mg of (±) -treo-2-hydroxy-3- (2-nitro-5-chlorophenylthio) -3- (4-methoxyphenyl) propionic acid in 5 ml ethanol and 5 ml 40 mg of 10% palladium on charcoal and 10% palladium on carbon were added. The mixture was copper-treated for 6 hours at room temperature under a hydrogen atmosphere. After completion of the reaction, the insoluble material was filtered off and the filtrate was concentrated in vacuo. The residue was recrystallized from dimethylformamide-ethanol. 269 mg of (±) -treo-2-hydroxy-3- (2-amino-5-chlorophenylthio) -3- (4-methoxyphenyl) propionic acid are obtained.

The product has the same physico-chemical characteristics as the material obtained in Preparation 2- (2).

Preparation 6 (1) 8.04 g of (±) -treo-2-hydroxy-3- (2-nitro-5-chlorophenylthio) -3- (4-methoxyphenyl) propionic acid are dissolved in 110 ml of methanol and 3 ml. 85 g of L-lysine hydrochloride are added to the solution. 21 ml of 1 N methanolic potassium hydroxide solution are added under ice-cooling, and the mixture is allowed to stand at room temperature. The precipitated crystalline material is filtered off (the resulting mother liquor is hereinafter referred to as mother liquor I).

The crystalline material (10.56 g) was recrystallized three times from a 1: 1 mixture of dimethylformamide / water; (the mother liquors obtained herein are hereinafter referred to as mother liquor II). 4.29 g of (+) - threo-2-hydroxy-3- (2-nitro-5-chlorophenylthio) -3- (4-methoxyphenyl) propionic acid L-lysine salt are obtained.

Mp 244-246 ° C (dec.).

The product obtained above (4.29 g) is suspended in water and the suspension is acidified with dilute hydrochloric acid and extracted with chloroform. The extract was washed with water, dried and concentrated in vacuo. The residue was recrystallized from isopropanol. 3.36 g of (+) - threo-2-hydroxy-3- (2-nitro-5-chlorophenylthio) -3- (4-methoxyphenyl) propionic acid are obtained.

Mp: 93-97 ° C.

U ⁺²⁰ : + 138.7 ° (C = 0.623, chloroform) Elemental analysis for C16H14O6NSCl.C3H7OH:

calcd: C, 51.41; H, 4.99; N, 3.16; S, 7.22;

Cl, 7.99;

Found: C, 51.25; H, 4.81; N, 3.30; S, 7.21;

Cl, 7.87.

-1 327

The resulting mother liquors I and II were combined and concentrated in vacuo. The crystalline precipitate was filtered off and recrystallized from ethanol-water (1: 1). 3.61 g of the L-lysine salt of (-) - threo-2-hydroxy-3- (2-nitro-5-chlorophenylthio) -3- (4-methoxyphenyl) propionic acid are obtained.

M.p .: 229-231 ° C (dec.).

The resulting salt (3.61 g) was converted to the free acid form using dilute hydrochloric acid and the product recrystallized from isopropanol. 2.80 g of (-) - threo-2-hydroxy-3- (2-nitro-5-chlorophenylthio) -3- (4-methoxyphenyl) propionic acid are obtained.

M.p. 92-97 ° C.

(α) D ²⁰ : -120.2 ° (C = 0.323, chloroform). Elemental analysis for C16H14O6NSCI.C3H7OH:

calcd: C, 51.41; H, 4.99; N, 3.16; S, 7.22;

Cl, 7.99;

Found: C, 51.12; H, 4.64; N, 3.68; S, 7.63;

Cl, 8.32.

(2-a) 362 g of (+) - threo-2-hydroxy-3- (2-nitro-5-chlorophenylthio) -3- (4-methoxyphenyl) -propionic acid are reacted with 5 - (3). and the crude product was recrystallized from methanol. 301 mg of (+) - threo-2-hydroxy-3- (2-amino-5-chlorophenylthio) -3- (4-methoxyphenyl) propionic acid are obtained.

The product has the same physico-chemical characteristics as the material obtained in Preparation 4— (1).

(2-b) 350 mg of (-) - threo-2-hydroxy-3- (2-nitro-5-chlorophenylthio) -3- (4-methoxyphenyl) -propionic acid is reacted with 5- (3). and the crude product was recrystallized from methanol. 260 mg of (-) - threo-2-hydroxy-3- (2-amino-5-chlorophenylthio) -3- (4-methoxyphenyl) propionic acid are obtained.

The product has the same physico-chemical characteristics as the product obtained in Preparation 4- (l).

Claims (12)

PATENT CLAIMS A process for the preparation of the 8-chloro-1,5-benzothiazepine derivatives of the formula I and their pharmaceutically acceptable acid addition salts, wherein: R ¹ is hydrogen or C 1-4 alkyl; R ² and R ³ are each C 1 -C 4 alkyl, characterized in that a compound of formula (II) or a salt thereof, wherein R ² and R ³ are as defined above, with a compound of formula (III) or a reactive derivative thereof, wherein R ¹ is as defined above, condensed and optionally converted to a pharmaceutically acceptable acid addition salt. (Priority: January 14, 1984) A process for the preparation of the 8-chloro-1,5-benzothiazepine derivatives of the formula I and their pharmaceutically acceptable acid addition salts, wherein R ¹ is C 1-3 alkyl, R ² and R ³ are each C 1 -C 4 alkyl, characterized in that a compound of formula (II) or a salt thereof, wherein R ² and R ³ are as defined above, with a compound of formula (III) or a reactive derivative thereof, wherein R ¹ is as defined above, condensed and optionally converted to a pharmaceutically acceptable acid addition salt. (Priority: June 3, 1983) A process for the preparation of a compound of formula I according to claim 1 wherein R ¹ is hydrogen or C 4 alkyl, R ² and R ³ are each C 1 -C 3 alkyl, wherein the substituents are suitably substituted. starting compounds. (Priority: January 14, 19B4) A process for the preparation of compounds of formula I according to claim 2, wherein R ¹ is C 1 -C 3 alkyl, R ² and R ³ are each C 1 -C 3 alkyl, characterized in that the appropriately substituted starting compounds are (Priority: June 3, 1983) The process for preparing compounds of formula I according to claim 3, wherein R ¹ is hydrogen, R ² and R ³ are each methyl or ethyl, characterized in that the appropriately substituted starting compounds are used. (Priority: January 14, 1984) A process for the preparation of a compound of formula (I) according to claim 4 wherein R ¹ is methyl or ethyl, R ² and R ³ are each methyl or ethyl, characterized in that the appropriately substituted starting compounds are used. . (Priority: June 3, 1983) The process for the preparation of compounds of formula I according to claim 6, wherein R ¹ is methyl or ethyl, R ^{2 is} methyl and R ^{3 is} methyl or ethyl, characterized in that the appropriately substituted starting compounds are used. (Priority: June 3, 1983) A process for the preparation of a compound of formula (fi) according to claim 7, wherein R ^{1 is} methyl or ethyl, R ² and R ^{3 are} methyl, wherein the appropriately substituted starting compounds are used. (Priority: June 3, 1983) The process for the preparation of a compound of formula I according to claim 7, wherein R ^{1 is} methyl, R ^{2 is} methyl 15 -1429 methyl or ethyl group and R ^3, characterized in that, from the appropriately substituted starting materials. (Priority: June 3, 1983) The process of claim 9, (+) - cis-2- (4-methoxyphenyl) -3-acetoxy-5- [2- (dimethylamino) ethyl] -8-chloro-2,3- dihydro-1,5-benzothiazepin-4 (5H) -one or its pharmaceutically acceptable acid addition salts, characterized in that (+) - cis-2- (4-methoxyphenyl) -3-hydroxy-5- [ 2- (dimethylamino) ethyl] -8-chloro-2,3-dihydro-1,5-benzothiazepin-4 (5H) -one is used. (Priority: June 3, 1983) The process according to claim 9, (+) - cis-2- (4-methoxyphenyl) -3-acetoxy-5- [N-methyl-N-ethylamino) ethyl] -8-chloro-2 , 3-dihydro-1,5-benzothiazepin-4 (5H) -one or its pharmaceutically acceptable acid addition salts, characterized in that (+) - cis-2- (4-methoxyphenyl) -3-hydroxy is used as starting material. 5- [2- (N5-Methyl-N-ethylamino) -ethyl] -8-chloro-2,3-dihydro-3,5-benzothiazepin-4 (5H) -one is used. (Priority: June 3, 1983) The process of claim 8, (+) - cis-2- (4-methoxyphenyl) -3-propionyloxy-5- [210 - (dimethylamino) ethyl] -8-chloro-2,3 -dihydro-1,3-benzothiazepin-4 (5H) -one or its pharmaceutically acceptable acid addition salts, characterized in that (+) - cis-2- (4-methoxyphenyl) -3-hydroxy-5 [2- (di15-methylamino) -ethyl) -8-chloro-2,3-dihydro-1,5-benzothiazepin-4 (5H) -one is used. (Priority: June 3, 1983)